Recent studies have been encouraging that viral control of hepatitis C virus infection is possible. Prophylactic vaccines or efficient immunotherapies are urgently needed to reduce the disease burden of this global epidemic. HCV infects estimated 170 million people worldwide, and causes significant morbidity in developed and developing countries. Various studies report an important role for both CD4+ and CD8+ in the control of HCV replication. However, the correlates of protective T-cell immunity and the mechanisms causal for T-cell failure in human HCV infection are not well understood. Clearly, the outcome is determined in the early phase of the disease, therefore it seems paramount to study the earliest events that set the stage for clearance versus persistence of the virus. . We propose here the analysis of CD8 and CD4 T-cell immunity in large cohorts of subjects with acute HCV infection and different transmission routes. Our central hypothesis is that acute HCV infection typically elicits both CD4 and CD8 T cell responses, but that early during infection critical changes in the quality of the T-cell response either lead to viral control or, in most subjects, persistence of the virus. To test this hypothesis we propose to define the functional profile of HCV-specific CD8 T-cells in the context of expression and activation of a combination of inhibitory molecules during acute HCV infection. We will use transcriptional profiles of HCV-specific T-cells during different stages of dysfunction together with gene expression signatures associated with distinct T-cell inhibitory molecules in order to define the complex events leading to a failed T-cell response. We will also determine the role of CD8 Tcells expressing the NK marker CDI61 as preliminary data suggest a role for this population in viral persistence. In addition to defining mechanisms leading to CD8 T-cell dysfunction and exhaustion, we will also investigate HCV-specific CD4+ T-cells that are equally, if not more, critical for viral control but have been investigated in much less detail. We have recently shown that we can identify HCV-specific CD4 Tcells in almost all subjects with acute HCV infection and have developed reagents to analyze these cells directly ex-vivo in our large cohorts of subjects with acute HCV infection. Dissection of the mechanisms of immune mediated control and T-cell failure will be an important contribution to guide the development of prophylactic vaccines or immunotherapies.